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PubMed2005

ATM expression in rectal cancers with or without preoperative radiotherapy.

Patients with ATM (Ataxia-Telangiectasia mutated) mutation show increased sensitivity to radiation and have a higher risk of developing malignancies. The present study aimed to investigate whether ATM expression was related to radiotherapy, and clinicopathological and biological variables in rectal cancers. ATM expression was immunohistochemically examined in 78 rectal cancers from patients who participated in a Swedish rectal cancer trial of preoperative radiotherapy. Of 78 patients, 44 underwent surgery alone, and 34 underwent both preoperative radiotherapy and surgery. Fifty-eight cases had normal rectal mucosa adjacent to the tumour. The results showed that, compared to normal mucosa, tumours had less nuclear (p=0.03) but more cytoplasmic expression of ATM (p=0.004). In tumours, less expression of ATM, either in the nucleus (p=0.07) or in the cytoplasm (p=0.02 for staining intensity, and p=0.07 for staining percentage), tended to be correlated with male patients. Also, ATM expression was not related to radiotherapy or other clinicopathological and biological variables (p>0.05). In conclusion, the pattern of ATM expression was changed from normal mucosa to tumour. Less expression of ATM may be related to males.

Adenocarcinoma↗
PubMed1999

ATM mutations in B-cell chronic lymphocytic leukemia.

Mutations in the ATM gene located on the long arm of chromosome 11 at 11q22-23 cause ataxia-telangiectasia, an autosomal recessive disorder that is associated with increased incidence of malignancy and, particularly, lymphoid tumors. A role for ATM in the development of sporadic T-cell chronic leukemias is supported by the finding of loss of heterozygosity at 11q22-23 and ATM mutations in leukemias carrying TCL-1 rearrangements. Approximately 14% of B-cell chronic lymphocytic leukemia (B-CLL), the most common adult leukemia, carry deletions of the long arm of chromosome 11 at 11q22-23. Loss of heterozygosity at 11q22-23 and, more recently, absence of ATM protein, have been associated with poor prognosis in B-CLL. To determine whether the ATM gene is altered in B-CLL, we have sequenced individual ATM exons in six B-CLL cases. We show that the ATM gene is mutated in a fraction of B-CLLs and that mutations can be present in the germ line of patients, suggesting that ATM heterozygotes may be predisposed to B-CLL.

Adult↗
PubMed2026

Germline ATM Testing in Hereditary Cancer Syndromes: Feedback from a Five-Year Center Cohort.

PURPOSE: Germline ATM pathogenic or likely pathogenic (P/LP) variants are increasingly recognized as clinically relevant in hereditary cancer predisposition, their integration into routine testing remains heterogeneous across countries. We describe the prevalence, tumor spectrum and relative risk associated with germline ATM P/LP variants in individuals with breast and pancreatic cancer. METHODS: We conducted a five-year retrospective (2019-2025) reanalysis of the ATM gene in 1,707 probands tested with hereditary breast and ovarian cancer (HBOC) or pancreatic cancer panels in our center. For all probands that underwent targeted ATM reanalysis, relative risks (RR) and odds ratios (OR) were calculated. Family-based segregation was performed when possible. RESULTS: Targeted ATM re-analysis identified 33 additional probands with P/LP variants, increasing diagnostic yield from 7.3% to 9.1% in HBOC and from 4.3% to 9.7% in pancreatic cancer. Among 22 breast-cancer probands, mean age at diagnosis was 47 years. Case-control comparison yielded OR 3.85 (95% CI 2.43-6.08; P=8.5×10-9) for breast cancer and OR 15.81 (95% CI 6.31-39.66; P=4.0×10-9) for pancreatic cancer. CONCLUSION: This work strengthens the role of ATM in cancer predisposition panels and supports its inclusion in French national hereditary cancer panel recommendations, together with implementation of appropriate surveillance and counseling for individuals harboring ATM P/LP variants.

ATM↗
PubMed2000

Aberrant splicing of the ATM gene associated with shortening of the intronic mononucleotide tract in human colon tumor cell lines: a novel mutation target of microsatellite instability.

Inherited mutations of the ATM gene are responsible for the human autosomal recessive disorder ataxia-telangiectasia (A-T) characterized by pleiotropic clinical manifestations. ATM mutations are also involved in the development of sporadic human cancers such as T-cell prolymphocytic leukemia and B-cell chronic lymphocytic leukemia. Little is known, however, on the association of ATM mutations with non-lymphoid malignancy. Here, we analyzed a panel of cell lines derived from human solid tumors for the presence of ATM mutations. PCR-SSCP analysis of 25 tumor cell lines revealed 50 sequence alterations in 16 cell lines. The most striking feature was a high frequency of deletions within the intronic mononucleotide tracts exclusively in the 5 colon tumor cell lines with microsatellite instability, which accounted for 62% of the sequence alterations observed here. Generation of aberrant splicing variants (497del22 or 1236del372) was associated with 2 such intronic deletions at splice acceptor sites preceding ATM exon 8 or exon 12, respectively. The level of ATM protein was partially depressed in the 3 cell lines where expression of protein-truncating 497del22 transcripts dominated. This implies that ATM is a novel mutation target of microsatellite instability where abnormal transcripts are generated indirectly by intronic mutations, which is distinct from the other mutation targets such as the type II TGF-beta receptor gene or BAX, where exonic repeats are directly affected.

Ataxia Telangiectasia Mutated Proteins↗
PubMed1999

New mutations, polymorphisms, and rare variants in the ATM gene detected by a novel SSCP strategy.

The gene for ataxia-telangiectasia, ATM, spans about 150 kb of genomic DNA. ATM mutations are found along the entire gene, with no evidence of a mutational hot spot. Using DNA as the starting material, we screened the ATM gene in 92 A-T patients, using an optimized single-strand conformation polymorphism (SSCP) technique that detected all previously known mutations in the polymerase chain reaction (PCR) segments being analyzed. To expedite screening, we sequentially loaded the SSCP gels with three different sets of PCR products that were pretested to avoid overlapping patterns. Many of the DNA changes we detected were intragenic polymorphisms. Of an expected 177 unknown mutations, we detected approximately 70%, mostly protein truncating mutations (that would have been detectable by protein truncation testing if RNA starting material had been available). Mutations have now been defined for every exon of the ATM gene. Herein, we present 35 new mutations and 34 new intragenic polymorphisms or rare variants within the ATM gene. This is the most comprehensive compilation of ATM polymorphisms assembled to date. Defining polymorphic sites as well as mutations in the ATM gene will be of great importance in designing automated methods for detecting mutations.

Ataxia Telangiectasia↗
PubMed2001

Increased frequency of ATM mutations in breast carcinoma patients with early onset disease and positive family history.

BACKGROUND: An increased incidence of breast carcinoma has been reported among relatives of individuals who are affected with the rare recessive disorder, ataxia-telangiectasia (A-T), and who are heterozygous for mutations in the ataxia-telangiectasia mutated (ATM) gene. However, most studies of breast carcinoma cases from the general population have failed to find a higher incidence of ATM mutations in cases when compared with controls. METHODS: Genomic DNA samples from 258 individuals were screened for mutations of all types in each of the 62 coding exons of the ATM gene; 142 of these were from breast carcinoma cases with a first-degree family history or early age at diagnosis, 35 were from cases selected for the presence of either known disease-related mutations (n = 25) or missense alterations of unknown consequences (n = 10) in BRCA1 or BRCA2, and 81 were from matched controls. RESULTS: A total of 12 individuals with ATM mutations were identified, 11 among 142 breast carcinoma cases (7.7%; 95% CI, 3.9-13.4%) and 1 among 81 controls (1.2%; 95% CI, 0.0-6.7%) (P = 0.06). All mutations detected were of the missense type; none were predicted to truncate the ATM protein. Among cases, mutations were found exclusively in patients with a family history of breast carcinoma (12.1%; 95% CI, 6.2-20.6%) (P = 0.02). Similar frequencies of ATM mutations were found in 35 additional cases selected for the presence of BRCA1 or BRCA2 mutations when compared with cases overall. CONCLUSIONS: ATM mutations, specifically missense mutations, are more common in breast carcinoma cases selected for first-degree family history and early age at diagnosis.

Adult↗
PubMed2004

Functional consequences of ATM sequence variants for chromosomal radiosensitivity.

The ATM [for ataxia-telangiectasia (A-T) mutated] protein plays a key role in the detection and cellular response to DNA double-strand breaks. Several single-nucleotide polymorphisms (SNPs) have been described in the ATM gene; however, their association with cancer risk or radiosensitivity remains to be fully established. In this study, the functional consequences of specific ATM SNPs on in vitro radiosensitivity, as assessed by micronuclei (MN) formation, were measured in lymphoblastoid cell lines established from 10 breast cancer (BC) patients carrying different ATM missense SNPs, six A-T patients, six A-T heterozygotes (A-T het), and six normal individuals. The BC, A-T het, and A-T cell line groups showed significantly higher mean levels of MN formation after exposure to ionizing radiation (IR) than did the group containing normal cell lines, with similar levels in the BC and A-T het groups. Within the BC lines studied, the group composed of the six carrying the linked 2572T>C (858F>L) and 3161C>G (1054P>R) variants had a higher level of MN after IR exposure compared to that observed in the remaining four BC or in the normal cell lines. This increase was not related to the constitutive ATM mRNA level, which was similar in these BC and the normal cell lines. Our results indicate that alterations in the ATM gene, including the presence of heterozygous mutations and the 2572C and 3161G variant alleles, are associated with increased in vitro chromosomal radiosensitivity, perhaps by interfering with ATM function in a dominant-negative manner.

Ataxia Telangiectasia↗
PubMed2005

Cancer risk according to type and location of ATM mutation in ataxia-telangiectasia families.

Epidemiological studies have indicated that ataxia-telangiectasia (AT) heterozygotes in AT families have an increased risk of cancer, particularly of breast cancer (BC). However, in BC case-control studies, no significant differences were found in the frequency of ATM mutations between patients and controls. In such studies missense mutations were found more frequently than truncating mutations, suggesting that the cancer risk depends on mutation type. To investigate this possibility, we assessed the risk of BC according to the type and position of the ATM truncating mutation in extended AT families. DNA or RNA that had been isolated from blood or buccal cells of AT children and their relatives was screened for ATM germ-line mutations using restriction endonuclease fingerprinting, the protein truncation test, fluorescence-assisted mismatch analysis, and direct sequencing. The standardized incidence ratio of cancer associated with ATM heterozygosity status and type of mutation was estimated. We tested for genotype-phenotype correlations by simulations, permuting mutations among parental branches. No significant difference was found in the relative risk of breast cancer or any other type of cancer based on mutation type. However, the occurrence of BC may be associated with truncating mutations in certain binding domains of the ATM protein (e.g., P53/BRCA1, beta-adaptin, and FAT domains; P = 0.006). In this limited sample set, the presence of missense or truncating ATM mutations was not associated with different cancer risks. The risk of BC appeared to be associated with the alteration of binding domains rather than with the length of the predicted ATM protein.

Ataxia Telangiectasia↗
PubMed2003

Role of p53 and ATM in photodynamic therapy-induced apoptosis.

BACKGROUND AND OBJECTIVES: Photodynamic therapy (PDT) induces cell death through a laser light-activated photosensitizer and is a treatment option for tumors resistant to radio- and chemo-therapy. STUDY DESIGN/MATERIALS AND METHODS: We investigated whether m-THPC-PDT induces cell death by necrosis and/or apoptosis, and whether these responses are modulated by p53 and/or ATM, two cancer-associated genes. Sensitivity of atm(+/+)p53(+/+), atm(+/+)p53(-/-), and atm(-/-)p53(-/-) mouse embryonic fibroblasts to m-THPC-PDT performed at a wavelength of 652 nm was determined by the MTT assay, trypan blue-exclusion, and the TUNEL and caspase3-cleavage apoptosis assays. c-Abl protein level was determined by immunoblotting. RESULTS: m-THPC-PDT rapidly induced cell death in a substantial fraction of cells by p53- and Ataxia telangiectasia mutated (ATM)-independent non-apoptotic processes. However, in the subset of apoptotic cells, apoptosis was reduced by loss of p53 and was even more reduced by the additional loss of ATM. Apoptosis correlated inversely with c-Abl level. CONCLUSIONS: p53 and ATM are not required for necrosis, but may be required for PDT-mediated apoptosis.

Animals↗
PubMed1996

Identification and chromosomal localization of Atm, the mouse homolog of the ataxia-telangiectasia gene.

Atm, the mouse homolog of the human ATM gene defective in ataxia-telangiectasia (A-T), has been identified. The entire coding sequence of the Atm transcript was cloned and found to contain an open reading frame encoding a protein of 3066 amino acids with 84% overall identity and 91% similarity to the human ATM protein. Variable levels of expression of Atm were observed in different tissues. Fluorescence in situ hybridization and linkage analysis located the Atm gene on mouse chromosome 9, band 9C, in a region homologous to the ATM region on human chromosome 11q22-q23.

Amino Acid Sequence↗
PubMed1999

Absence of mutations in ATM, the gene responsible for ataxia telangiectasia in patients with cerebellar ataxia.

Ataxia-telangiectasia (AT) is an autosomal recessive multisystem disorder presenting in childhood with progressive cerebellar ataxia, oculocutaneous telangiectasia, immune deficiency, radiosensitivity, and cancer predisposition. The gene for AT, designated ATM (AT, mutated) encodes a protein with a carboxy-terminal phosphoinositide-3 kinase domain which is involved in cell cycle checkpoints and other responses to genotoxic stress. Most of the patients with the classical AT phenotype are homozygous or compound heterozygous for severe mutations causing truncation or destabilization of the ATM protein. Patients with a milder forms of disease, called AT variants, have been found to be either homozygous for milder mutations or compound heterozygotes for null alleles and mild mutations. In order to define the clinical phenotype of patients homozygous (or compound heterozygotes) for other, milder mutations, we decided to search for ATM mutations in patients with either sporadic or familial idiopathic ataxia. Thirty-four patients with idiopathic cerebellar ataxia, aged 3-77 years, were screened for mutations in the ATM coding region. There were 12 familial cases. None of the patients had abnormal immunoglobulin or alpha-fetoprotein levels, and none had mutations in the ATM coding region. In this heterogeneous group of patients with cerebellar ataxia we found no mutations in the ATM gene. We conclude that mutations in the ATM gene are probably not a common cause for cerebellar ataxia other than AT.

Adolescent↗
PubMed1998

A double missense mutation in the ATM gene of a Dutch family with ataxia telangiectasia.

Ataxia telangiectasia (AT) is an autosomal recessive disorder characterized by cerebellar ataxia, telangiectasia, immunodeficiency, elevated alpha-fetoprotein levels, chromosomal instability, predisposition to cancer, and radiation sensitivity. We report the identification of a new, double missense mutation in the ataxia telangiectasia gene (ATM) of a Dutch family. This homozygous mutation consists of two consecutive base substitutions in exon 55: a T-->G transversion at position 7875 of the ATM cDNA and a G-->C transversion at position 7876. These transversions were confirmed by polymerase chain reaction/primer-induced restriction analysis with CelII. The double base substitution results in an amino acid change of an aspartic acid to a glutamic acid at codon 2625 and of an alanine to a proline at codon 2626 of the ATM protein. Both amino acids are conserved between the ATM protein and its functional homolog, the Atm gene product in the mouse. Furthermore, the Chou-Fasman and Robson predictions both demonstrate a change in the secondary structure of the ATM protein carrying the D2625E/A2626P mutation. These findings suggest that the double base substitution in the ATM gene is a disease-causing mutation.

Adolescent↗
PubMed2006

A role for atm in E-cadherin-mediated contact inhibition in epithelial cells.

Ataxia telangiectasia is a hereditary pleiomorphic syndrome caused by loss of Atm, a phosphoprotein involved in multiple signaling pathways. Here, we propose a novel role for atm in cultured epithelial cells, namely the regulation of cell growth by contact inhibition. We show that atm is upregulated in epithelial cells reaching confluence. Conditional expression of the PI 3-Kinase domain of atm in non-confluent Tac-2 epithelial cells increases the expression of the anti-proliferative gene Tis-21 and downregulates key cell cycle regulator genes, such as cyclins A, B1, B2, E and E2. Finally, we demonstrate that upregulation of atm, and thus Tis-21, in confluent Tac-2 cells can be inhibited by an E-cadherin antibody blocking specifically homophilic E-cadherin interactions between adjacent cell surfaces. Altogether, these results suggest that atm could participate in a molecular pathway linking extracellular signalling to cell cycle control and may help further clarify the role of Atm in epithelial cell biology and carcinogenesis.

Animals↗
PubMed2005

Molecular cloning and functional characterization of zebrafish ATM.

Ataxia-telangiectasia mutated (ATM) is the gene product mutated in ataxia-telangiectasia (A-T), which is an autosomal recessive disorder with symptoms including neurodegeneration, cancer predisposition and premature aging. ATM is thought to play a pivotal role in signal transduction in response to genotoxic DNA damage. To study the physiological and developmental functions of ATM using the zebrafish model system, we cloned the zebrafish homolog cDNA of human ATM (hATM), zebrafish ATM (zATM), analyzed the expression pattern of zATM during early development, and further developed the system to study loss of zATM function in zebrafish embryos. Employing information available from the zebrafish genomic database, we utilized a PCR-based approach to isolate zATM cDNA clones. Sequence analysis of zATM showed a high level homology in the functional domains of hATM. The putative FAT, phosphoinositide 3-kinase-like, and FATC domains of zATM, which regulate ATM kinase activity and functions, were the most highly conserved regions, exhibiting 64-94% amino acid identity to the corresponding domains in hATM, while exhibiting approximately 50% amino acid identity outside these domains. The zATM gene is expected to consist of 62 coding exons, and we have identified at least 55 exons encompassing more than 100kb of nucleotide sequence, which encodes about 9 kb of cDNA. By in situ hybridization, zATM mRNA was detected ubiquitously with a dramatic increase at the 18-somite stage, then more specifically in the eye, brain, trunk, and tail at later stages. To inhibit zATM expression and function, we designed and synthesized splice-blocking antisense-morpholino oligonucleotides targeting the phosphoinositide 3-kinase-like domain. We demonstrated that this knockdown of zATM caused abnormal development upon ionizing radiation-induced DNA damage. Our data suggest that the ATM gene is structurally and functionally conserved in vertebrates from zebrafish to human.

Aging↗
PubMed2004

The Drosophila ATM ortholog, dATM, mediates the response to ionizing radiation and to spontaneous DNA damage during development.

Cells of metazoan organisms respond to DNA damage by arresting their cell cycle to repair DNA, or they undergo apoptosis. Two protein kinases, ataxia-telangiectasia mutated (ATM) and ATM and Rad-3 related (ATR), are sensors for DNA damage. In humans, ATM is mutated in patients with ataxia-telangiectasia (A-T), resulting in hypersensitivity to ionizing radiation (IR) and increased cancer susceptibility. Cells from A-T patients exhibit chromosome aberrations and excessive spontaneous apoptosis. We used Drosophila as a model system to study ATM function. Previous studies suggest that mei-41 corresponds to ATM in Drosophila; however, it appears that mei-41 is probably the ATR ortholog. Unlike mei-41 mutants, flies deficient for the true ATM ortholog, dATM, die as pupae or eclose with eye and wing abnormalities. Developing larval discs exhibit substantially increased spontaneous chromosomal telomere fusions and p53-dependent apoptosis. These developmental phenotypes are unique to dATM, and both dATM and mei-41 have temporally distinct roles in G2 arrest after IR. Thus, ATM and ATR orthologs are required for different functions in Drosophila; the developmental defects resulting from absence of dATM suggest an important role in mediating a protective checkpoint against DNA damage arising during normal cell proliferation and differentiation.

Animals↗
PubMedDate not supplied

Functional consequences of sequence alterations in the ATM gene.

The product of the gene (ATM) mutated in the human genetic disorder ataxia-telangiectasia (A-T) is a high molecular weight, protein ( approximately 350kDa) containing a C-terminal protein kinase domain and a number of other putative domains not yet functionally defined. The majority of ATM gene mutations in A-T patients are truncating, resulting in prematurely terminated products that are highly unstable. Missense mutations within the kinase domain and elsewhere in the molecule alter the stability of the protein and lead to loss of protein kinase activity. Only rarely are patients observed with two missense mutations and this gives rise to a milder disease phenotype. Evidence for a dominant interfering effect on normal ATM kinase activity has been reported in cell lines transfected with missense mutant ATM and in cell lines from some A-T heterozygotes. The dominant negative effect of mutant ATM is manifested by an enhancement of cellular radiosensitivity and may be responsible for the cancer predisposition observed in carriers of ATM missense mutations. In this review, we explore the domain structure of the ATM molecule, sites of interaction with other proteins and the consequences of specific amino acid changes on function.

Amino Acid Sequence↗
PubMed2006

ATM-mediated response to DNA double strand breaks in human neurons derived from stem cells.

Ataxia-telangiectasia (A-T) is a multi-system genomic instability syndrome that is caused by loss or inactivation of the ATM protein kinase. ATM is largely nuclear in proliferating cells, and activates an extensive network of pathways in response to double strand breaks (DSBs) in the DNA by phosphorylating key proteins in these pathways. The prominent symptom of A-T is neuronal degeneration, making the elucidation of ATM's functions in neurons essential to understanding the disease. It has been suggested that ATM is cytoplasmic in neurons and functions in processes that are not associated with the DNA damage response. Recently we showed that in human neuron-like cells obtained by in vitro differentiation of neuroblastomas, ATM was largely nuclear and mediated the DSB response as in proliferating cells. We have now extended these studies to two additional model systems: neurons derived from human embryonic stem cells, and cortical neurons derived from neural stem cells. The results substantiate the notion that ATM is nuclear in human neurons and mediates the DSB response, the same as it does in proliferating cells. We present here unique and powerful model systems to further study the ATM-mediated network in neurons.

Ataxia Telangiectasia↗
PubMed2006

MDC1 maintains genomic stability by participating in the amplification of ATM-dependent DNA damage signals.

MDC1 functions in checkpoint activation and DNA repair following DNA damage. To address the physiological role of MDC1, we disrupted the MDC1 gene in mice. MDC1-/- mice recapitulated many phenotypes of H2AX-/- mice, including growth retardation, male infertility, immune defects, chromosome instability, DNA repair defects, and radiation sensitivity. At the molecular level, H2AX, MDC1, and ATM form a positive feedback loop, with MDC1 directly mediating the interaction between H2AX and ATM. MDC1 binds phosphorylated H2AX through its BRCT domain and ATM through its FHA domain. Through these interactions, MDC1 accumulates activated ATM flanking the sites of DNA damage, facilitating further ATM-dependent phosphorylation of H2AX and the amplification of DNA damage signals. In the absence of MDC1, many downstream ATM signaling events are defective. These results suggest that MDC1, as a signal amplifier of the ATM pathway, is vital in controlling proper DNA damage response and maintaining genomic stability.

Adaptor Proteins, Signal Transducing↗